The drug delivery system (DDS) is one of the methods of enhancing the effect of pharmacotherapeutics. It employs a liposome preparation which is composed of vesicles of phospholipid bilayer structure and a drug supported thereby. The liposome preparation is now attracting keen attention because of its ability to support a drug on the liposome membrane or in the liposomal aqueous phase. It is common practice to chemically modify liposomes with functional groups, thereby changing liposomes into a prodrug which alters the drug's inherent behavior in blood such that the drug has an extended half-life and becomes stabilized in blood. Unfortunately, the prodrug prepared in this manner often exhibits toxicity and decreases in drug effect.
The foregoing disadvantage is overcome if a drug is supported by liposomes. In this case, liposomes help maintain the effect of the drug, extend the half-life of the drug, and improve the stability of the drug in blood, without noticeable side effects. The liposome preparation, with liposome's particle size adequately controlled and liposome's surface coated with a hydrophilic polymer, is not readily captured by the reticuloendotherial system (RES) present in the liver, spleen, lymph node, and lung, through which liposomes are excreted. Therefore, it stays longer in blood and accumulates in lesions (for passive targeting), thereby improving its therapeutic effect.
The pharmacokinetics of any drug enclosed in liposomes greatly is dependent on the behavior of liposomes in blood. In this case, it has been reported that the liposomal pharmacokinetics and distribution in the tissue are largely affected by the particle diameter and size distribution of liposomes. (See Non-Patent Document 1, for example.) These parameters are important for liposome preparations, and hence they are controlled in the particle size regulating step in the manufacturing process. Thus, the particle diameter regulation step is one of the most important steps in production of liposome preparations whose characteristic properties are determined by it.
The particle diameter of liposome preparations is established according to the object of therapy and the disease to be cured. To achieve the established particle diameter, the liposome forming step or the ensuing particle diameter regulating step was conducted. The particle diameter regulating step usually employs an extruder; it is repeated several times until the required particle diameter is achieved. The number of the particle diameter regulating steps is finally determined based on results of the liposomal diameter at each step obtained in the preliminary investigation for particle diameter regulating step. On the other hand, it has been reported that the particle diameter of liposomes varied depending on pressure applied in the particle diameter regulating step. (See Non-Patent Document 2, for example.) From above findings, if an excess pressure fluctuation occurs for some reason, the liposome with not-intended particle diameter is obtained. From this reason, there is no way of judging whether or not the desired particle diameter has been reached in the particle diameter regulating step in current known liposome production method.
Most liposome preparations are required to be germ-free because they are usually administered directly into the vein. Therefore, they should be produced under strictly sterile condition and germ related risk during manufacturing process should be reduced as far as possible. To meet this requirement, liposome preparations should be produced in a closed space because they cannot be sterilized after production. In practice, however, the production process for liposome is complicated and as specification as final product and intermediate product during manufacturing process, the particle diameter is set. Sampling of an intermediate product for measurement of particle diameter breaks the closed space and this procedure makes the sterile condition be endangered.
In order to provide liposome preparations of high quality, it is necessary to accomplish sterile operation and have a system for measuring and monitoring the particle diameter accurately in real time without contact with samples.
Meanwhile, the concept of Process Analytical Technology (PAT) is recently attracting attention. This concept has stemmed from the fact that the production technology tends to lag behind the technologies achieved in research and development and the underdeveloped production technology adversely affects product quality and quality control system, causing final products to be rejected. Thus it is necessary to apply the latest technology to the critical step that affects product quality in the manufacturing process so that the product is monitored continuously in real time to avoid rejections. Moreover, in this way it will be possible to simplify the off-line inspection step.
The measuring technique to which PAT is currently applied includes, for example, spectroscopic analysis by infrared absorption and Raman scattering, electronic sound spectroscopic analysis, X-ray spectroscopic analysis, pH measurement, conductivity measurement, potential measurement, and dielectric measurement. Among these techniques, spectroscopic analysis by near infrared absorption is widely used to determined mixing homogeneity, to measure moisture content, and to measure the content of specific components.
Non-Patent Document 1:    Biochim. Biophys. Acta. 1990, 99-107, 1994
Non-Patent Document 2:    Biophys. J. 74, 1996-3002, 1998